Project Summary Alzheimer's Disease (AD) is the major public health crisis of our time. Based on the rationale that treatments are more likely to be effective before significant cognitive impairment has accrued, there is increased focus on intervening in preclinical or early prodromal stages. A major challenge for clinical trials in these populations is development of tools to determine if these interventions are effective. As the earliest neurodegenerative changes of AD are thought linked to the development of pathology within the medial temporal lobe (MTL), measures of episodic memory and imaging of this region may play a critical role in serving as a means for disease monitoring. However, ?normal? aging is also associated with both structural and functional alterations of the MTL, and episodic memory is one of the domains most saliently implicated in age-associated cognitive decline. The major goal of this proposal is to identify MTL-related features that distinguish normal aging from preclinical AD, as well as the factors that influence these differences. In light of structural, functional, and cognitive overlap in normal aging and preclinical AD, a more granular examination is necessary to better distinguish these conditions. Doing so is essential for effective disease monitoring that dissociates age-effects from those of evolving AD. Critically, the MTL consists of a number of inter-related subregions that have been associated with different aspects of memory and may be selectively vulnerable to aging versus preclinical AD. However, despite decades of work focused on the cognitive neuroscience of memory loss with aging, this more granular understanding of specific changes that occur within the MTL and related networks is lacking and the literature conflicting. We will address a number of methodologic issues with the prior literature that may account for this inconsistency. First, we will leverage our extensive experience in development of methods for MTL structural and functional measurement and take advantage of the improved resolution of 7 Tesla (T) MRI imaging over more standard clinical or research MRI scans. Second, we will obtain amyloid imaging to determine the presence preclinical AD, allowing us to isolate aging effects on its own. Third, we will comprehensively account for other factors that may influence MTL changes, including cerebrovascular disease (CVD), presence of neurofibrillary tangle (NFT) pathology independent of preclinical AD, and genetic factors. We will obtain sensitive markers of CVD with 7T MRI, NFT burden with Tau PET imaging, and SNPs associated with AD risk. Fourth, we will examine the cognitive effects of these changes with experimental memory measures. We anticipate that the detailed understanding of the effect of age on MTL structure and function will allow for definition of monitoring targets of preclinical AD and significantly enhance our understanding of mechanisms underlying age-associated memory decline.